Degeneration of septal neurons in Alzheimer's disease (AD) results in abnormal information processing at cortical circuits and consequent brain dysfunction. The septum modulates the activity of archicortical (e.g. hippocampal) and neocortical circuits and is crucial to the initiation and occurrence of rhythmical cortical activities such as the hippocampal theta rhythm which plays an important role in processing sensory information and memory. Until recently, only cholinergic and GABAergic septal neurons were believed to exist and project to the hippocampus. Our laboratory characterized a third population of septal neurons that project to the hippocampus and use glutamate as a neurotransmitter. Their function and vulnerability to AD remains unknown. Because glutamatergic synapses are involved in learning and memory processes, septal glutamatergic neurons are critically positioned to play a key role in the cognitive processes impaired by AD. Our preliminary data indicate that septal glutamatergic neurons are killed by amyloid p peptides (Ap) This loss of septal glutamatergic neurons is a new finding that can revolutionize our understanding of AD. The goal of our research is to understand the function of the septo-hippocampal glutamatergic system and its involvement in AD. To achieve this goal, we hypothesize that glutamatergic neurons, rather than cholinergic neurons, provide the main septal excitatory input to the hippocampus necessary for the generation of a theta rhythm that facilitates plastic processes, and that the dysfunction of these glutamatergic neurons plays a central role in the septal degeneration and temporal lobe hypofunction typically observed in AD patients. Accordingly, we will use a combination of immunohistochemistry, stereology, neuronal tracers, in vitro and in vivo electrophysiological approaches to carry out specific aims (SA) that will determine: the postsynaptic effects of the septo-hippocampal glutamatergic projection (SA1), the vulnerability of the septal glutamatergic neurons to amyloid p peptides (Ap) (SA2), and the firing patterns of identified glutamatergic septal neurons during hippocampal theta rhythm and large irregular activity (LIA) and their alterations induced by Ap (SA3). Overall, the proposed experiments will give us insight into manipulating septal glutamatergic neurotransmission as a means of regulating information processing by hippocampal networks and restoring the AD-vulnerable cognitive processes they serve.